Development of a numerical tool to model sonoporation of endothelial cell membrane Sonoporation is an acoustical method to increase the permeability of membranes, in particular endothelial cell membranes that line the inner walls of blood vessels, in order to extravasate large drug molecules. Enhanced permeabilization can be obtained due to the mechanical stress generated when microbubbles in the form of ultrasound contrast agents are excited inside a micro vessel using ultrasound. The underlying fluid dynamics forces responsible for this stress can come from various sources viz. shock waves emitted upon bubble collapse, acoustic transients emitted from the bubble, shearing forces due to acoustic streaming, or micro jets from aspherical bubble collapse. A major impediment in rapid development of this technology is the lack of complete understanding of the underlying mechanisms, i.e. the details of the bubble and cells interaction as well as the sonoporation mechanism. Numerical modeling coupled with fundamental experiments can help bridge this gap. In this SBIR work, we propose to develop a computational tool to model sonoporation of endothelial cell membrane using acoustically activated ultrasound contrast agents. The numerical model will address non-spherical bubble dynamics in a confined environment like a micro vessel. It will also model the vessel response, deformation, and potential mechanical micro-failure and sonoporation. We will model the acoustic propagation through the inhomogeneous biological medium using a compressible Navier-Stokes solver augmented with a Lagrangian mixed cell approach to track the interface between phases and to capture the deformations of the microbubbles. A structural solver that treats the blood vessel as a viscoelastic material along with a contact surface model to simulate a realistic endothelial cell membrane will be used to capture the deformation of the membrane and a fluid structure coupling will be used to couple the bubble and membrane dynamics. In Phase I, we will concentrate on single non-spherical bubble dynamics interaction with the vessel and validate the numerical model using experimental data available in the literature. In Phase II we will collaborate with University of Washington to further validate the developed model with controlled sonoporation experiments in an environment closer to clinical applications. We will further develop the model in Phase II to include bubble clouds containing thousands of microbubbles by tracking individual bubbles in a Lagrangian framework. The resulting computational tool developed under this SBIR program will be integrated within our current software package, 3DYNAFS as an add- on module, commercialized and offered to researchers and sonoporator manufacturers.
The product resulting from this project will be a design tool that can be used by sonoporator device developers, clinical practitioners, and researchers. The tool will enable one to perform parametric studies that can shed light on the fluid dynamic forces responsible for sonoporation. It will allow to explore a wide range of parameters to identify promising experimental and practical configurations and setups, and to help optimize sonoporators for achieving increased drug uptake with minimum cell damage.
